P2X7: a receptor with a split personality that raises new hopes for anti-cancer therapy

In a recent paper, Valerie Vouret-Craviari and coworkers show that controlled activation of the P2X7 receptor (P2X7R) inhibits growth of non-small cell lung cancer (NSCLC), promotes tumor regression in association with anti-PD-1 antibodies, and confers long-lasting CD8+ lymphocyte-mediated immunity [1]. The pathophysiological function of the P2X7 receptor (P2X7R) is still a puzzle 25 years after its cloning [2] and even longer since its role in immunity and cancer was first postulated [3] [4] [5]. For almost 3 decades, investigators’ attention focused on the peculiar property of this receptor to trigger cytotoxicity, by necrosis, apoptosis, or pyroptosis, depending on the given cell type and the experimental conditions [6]. The (apparently) unavoidable association between P2X7R gating and cell death depends on the peculiar ability of this receptor to open a non-selective plasma membrane pathway (the so-called macropore, whether intrinsic to the receptor or simply activated by the receptor is not clear), allowing uncontrolled fluxes of aqueous solutes across the plasma membrane [7].